The Molecular Mechanism of Sex Hormones on Sertoli Cell Development and Proliferation

Abstract

Sustaining and maintaining the intricate process of spermatogenesis is liable upon hormones and growth factors acting through endocrine and paracrine pathways. The Sertoli cells (SCs) are the major somatic cells present in the seminiferous tubules and are considered to be the main regulators of spermatogenesis. As each Sertoli cell supports a specific number of germ cells, thus, the final number of Sertoli cells determines the sperm production capacity. Similarly, sex hormones are also major regulators of spermatogenesis and they can determine the proliferation of Sertoli cells. In the present review, we have critically and comprehensively discussed the role of sex hormones and some other factors that are involved in Sertoli cell proliferation, differentiation and maturation. Furthermore, we have also presented a model of Sertoli cell development based upon the recent advancement in the field of reproduction. Hence, our review article provides a general overview regarding the sex hormonal pathways governing Sertoli cell proliferation and development.

Keywords: Sertoli cells; fertility; sex hormone; spermatogenesis; testis.

Figure 1

Flow chart description the control of hypothalamus–pituitary–testis axis on Sertoli cell proliferation. The hypothalamic GnRH modulates the biosynthesis and secretion of pituitary hormones i.e., LH and FSH. LH induces secretion of testosterone in Leydig cells and is involved in the late Sertoli cell proliferation period, followed by negative feedback reducing GnRH and LH production. FSH primarily stimulates the seminiferous tubules to form steroid hormones such as inhibin and further sustain the process of spermatogenesis. Steroid hormones i.e., testosterone and inhibin exert negative feedback effects on GnRH.

Figure 2

Flow chart diagram representing the factors/pathways involved in Sertoli cell development and proliferation. This figure summarized the role of sex hormones, hormones other than sex hormones and non-hormonal pathways that have been implicated in Sertoli cell development.

Figure 3

FSH and testosterone signaling pathways in Sertoli cell proliferation. Initially FSH binding to the FSH receptor causes receptor coupled G proteins to activate adenylate cyclase (AC) and increase intracellular cAMP levels. Multiple factors can be activated by cAMP in Sertoli cells including PKA that can phosphorylate a number of proteins and also regulate the expression and activity of numerous transcription factors including CREB. FSH also causes Ca²⁺ influx into Sertoli cells that is mediated by cAMP and perhaps PKA modification of surface Ca²⁺ channels. Depolarization of the cell is also involved in Ca²⁺ influx. Elevated Ca²⁺ levels can activate calmodulin and CaM kinases that have multiple potential downstream effects including the phosphorylation of CREB. During puberty, FSH activates the MAP kinase cascade and ERK kinase in Sertoli cells most likely via cAMP interactions with guanine nucleotide exchange factors (GEFs) and activation of Ras-like G proteins. ERK is capable of activating transcription factors including SRF, c-jun and CREB. FSH and cAMP likely act through GEFs to activate PI3-K and then phosphoinositide dependent protein kinase (PDK1) and PKB in Sertoli cells. FSH also mediates the induction of PLA₂ and the subsequent release of arachadonic acid (71, 72).